A whole class of gastric Na/K pump inhibitors, widely used as antiulcer drugs, are benzimidazole compounds containing in their skeleton a sulfoxide moiety. Omeprazole, Lansoprazole, Pantoprazole and Rabeprazole are the most famous members of this class of compounds and several patents have appeared dealing with their synthesis.
Whatever the staring materials are, the final step of their preparation is invariably the oxidation of the corresponding sulfide 1, as represented in the following Scheme 1:
in which each substituent of the above formulae has, for the drugs just mentioned, the meaning reported here below:
Omeprazole2aR1═R2═R3═R4═Me; n=1Lansoprazole2bR1═Me; R2═R4═H; R3═CH2CF3; n=0Pantoprazole2cR1═OMe; R2═H; R3═Me; R4═CHF2; n=1Rabeprazole2dR1═Me; R2═R4═H; R3═CH2CH2CH2OCH3; n=0So far, several methods for performing the above oxidation have been described in the literature. Such methods use different oxidizing agents and/or conditions of reaction (see as an example WO99/47514 and the references cited therein).
Particularly relevant for the present invention are those oxidations that use hydrogen peroxide as oxidizing agent, in the presence of a transition metal compound as catalyst. For example EP302720 describes the use of vanadium catalysts for the oxidation of sulfides 1 with hydrogen peroxide, whereas ES2036948 claims as catalyst for the same transformation phosphotungstic acid, ammonium molibdate, sodium tungstate, phosphomolibdic acid and silicotungstic acid. ES2105953 specifically claims phosphomolibdic acid for this transformation.
All these oxidation methods show serious problems of impurity formation due to overoxidation As a matter of fact overoxidation of 1 can form byproducts such as the sulfone 3 or the N-oxides 4 e 5, as represented in the following Scheme 2:
Other examples of the same kind of oxidation are disclosed in WO02/074766 and WO01/21617.
In particular, WO02/074766 describes the preparation of Lansoprazole from the corresponding sulfide through the reaction of hydrogen peroxide catalyzed by phenylseleninic acid. In this case the use of a toxic selenium catalyst, combined with that of halogenated solvents as reaction media, limits the industrial applicability of the process.
On the other hand, WO01/21617 discloses the use of the same oxidant but in the presence of a different catalyst, namely MeReO3, in an alcoholic medium.
Unfortunately, even if this method is very good as regards selectivity, it is hardly applicable on industrial scale, both for the large quantities of very expensive catalyst employed and for the low temperatures at which the reaction has to be performed. In fact, according to the above patent application, it is possible to achieve the good yields and the high purity of the final sulfoxide reported therein, only by keeping the amount of catalyst and the reaction temperature within specific values, rather disadvantageous from the industrial point of view.
As stated in the description, the catalyst may be used in an amount from 0.1 to 10 moles % but, preferably, from 1 to 5 mole % (see page 12, lines 18–20) with respect to the starting material In addition, the amount of catalyst effectively used in example 1—the only one according to the invention—is about 4 mole %. In the same patent application it is stated that “ . . . when the methyltrioxorhenium catalyst was used at the amount of 1 mole % or less, yield was decreased” (see page 18, lines 11–13).
As a matter of fact, the whole application teaches that an amount of catalyst greater than 1 mole % is required for obtaining satisfactory results.
But even more relevant for the present discussion are the temperature requirements.
In fact the description of WO01/21617 states that the oxidizing reaction is carried out at a temperature from −40° C. to 0° C., preferably from −30° C. to −15° C. (see page 13, lines 4 and 5) while all the examples are performed at a temperature of −20 to −30° C.
The main teaching that a skilled in the art could have got by reading the patent application in object is that a temperature lower than 0° C. was necessary in order to reduce the formation of by-products and achieve good results. In other words, the content of WO01/21617 would have seriously discouraged any attempt to perform the same oxidation at a higher temperature and with a lower amount of catalyst.
In conclusion, in view of the above discussion on the relevant prior art, it would be highly desirable to dispose of a selective and industrially feasible method of oxidation of sulfide 1 to sulfoxide 2, that would produce satisfactory yields of a highly pure final product, by using a very low amount of catalyst and by performing said oxidation at a temperature compatible with standard industrial equipments.
Notwithstanding the opposite teaching of the closest art (WO01/21617), it has now been found that the oxidation of sulfide 1 to the desired sulfoxides 2 disclosed in said patent application can be run with good selectivity and recovery of the desired product by using lower catalyst loadings and temperatures higher than 0° C. The opportunity of lowering the catalyst loading is particularly advantageous both in terms of reduced contamination of the final product with heavy metals and in terms of cost of the catalyst. On the other hand, the chance of performing the reaction at higher temperatures avoids the need of special expensive low temperature equipments, allowing the use of ordinary industrial reactors for the synthesis. As a matter of fact, the present process represents a cheaper and industrially practicable advantageous alternative for preparing the class of compounds in object.